Optimization of Chromone-2-carboxamide Melanin Concentrating Hormone Receptor 1 Antagonists: Assessment of Potency, Efficacy, and Cardiovascular Safety
| Autor: | Gilbert Diaz, Lee C. Preusser, Ann Mikhail, Christopher A. Ogiela, Lynch John K, Philip R. Kym, Lisa M. Hernández, Dariusz Wodka, Gang Zhao, Doug H. Falls, Eugene N. Bush, James S. Polakowski, Andrew S. Judd, Robin Shapiro, Hing L. Sham, James J. Napier, Christine A. Collins, Kennan C. Marsh, Victoria Knourek-Segel, Glenn A. Reinhart, Thomas J Campbell, Sevan Brodjian, Michael E. Brune, Brian A. Droz, Mathew M. Mulhern, Kathryn Houseman, Regina M. Reilly, Brian D. Dayton, Ryan M. Fryer, James T. Limberis, Rajesh R. Iyengar, Freeman Jennifer C |
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| Rok vydání: | 2006 |
| Předmět: |
medicine.medical_specialty
Potassium Channels medicine.drug_class Acylation hERG Blood Pressure Carboxamide Cell Line Rats Sprague-Dawley Electrocardiography Mice Structure-Activity Relationship Dogs Pharmacokinetics Heart Rate In vivo Internal medicine Drug Discovery medicine Animals Potency Benzodioxoles Receptors Somatostatin biology Chemistry Body Weight Antagonist Potassium channel Rats Melanin-concentrating hormone receptor Mice Inbred C57BL Endocrinology Cardiovascular Diseases Chromones Area Under Curve biology.protein Molecular Medicine Calcium Female Indicators and Reagents Half-Life |
| Zdroj: | Journal of Medicinal Chemistry. 49:6569-6584 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm060683e |
| Popis: | Evaluation of multiple structurally distinct series of melanin concentrating hormone receptor 1 antagonists in an anesthetized rat cardiovascualar assay led to the identification of a chromone-2-carboxamide series as having excellent safety against the chosen cardiovascular endpoints at high drug concentrations in the plasma and brain. Optimization of this series led to considerable improvements in affinity, functional potency, and pharmacokinetic profile. This led to the identification of a 7-fluorochromone-2-carboxamide (22) that was orally efficacious in a diet-induced obese mouse model, retained a favorable cardiovascular profile in rat, and demonstrated dramatic improvement in effects on mean arterial pressure in our dog cardiovascular model compared to other series reported by our group. However, this analogue also led to prolongation of the QT interval in the dog that was linked to affinity for hERG channel and unexpectedly potent functional blockade of this ion channel. |
| Databáze: | OpenAIRE |
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